Filarial nematodes are arthropod-transmitted parasites of vertebrates including humans. Infection is long-term with individual worms surviving for in excess of five years. The consensus of opinion amongst workers in this field is that such longevity reflects suppression or modulation of the host immune system and indeed “defects” in immune responsiveness have been revealed in infected individuals. These defects incorporate impairment of lymphocyte proliferation and bias in production of both cytokines and antibodies. With respect to cytokines the bias can be shown in reduced production of the pro-inflammatory IFN-γ and increased production of the anti-inflammatory IL-10. For antibodies, there are imbalances in IgG subclasses—greatly elevated IgG4 (an antibody of little value in eliminating pathogens due to an inability to activate complement or bind with high affinity to phagocytic cells); decreases in other IgG subclasses. Overall therefore, the picture is of an immune response demonstrating a somewhat suppressed, anti-inflammatory phenotype which is often classified as “TH-2” (“TH” is derived from a category of T-lymphocyte referred to as “helper”). It has been speculated that such a phenotype is conducive to both parasite survival and host health, the latter by limiting pathology resulting from an over-aggressive immune response. Consistent with this, it is noteworthy that the majority of humans who harbour these parasites demonstrate little evidence of detrimental pathology.
Modulation of the host immune system is likely to involve the active participation of filarial nematodes and hence considerable effort has been spent in characterising the biological properties of molecules secreted by the worms.
Goodridge et al. in the Journal of Immunology, 2001, 167, discuss modulation of macrophage cytokine production by ES-62 resulting in suppression of the production of pro-inflammatory cytokines which may contribute to the immunomodulatory properties of ES-62 that drive the generation of immune responses with an anti-inflammatory and/or TH-2 phenotype. Although this article provides a rationale for the changes seen in the immune response, no guidance is provided on whether ES-62 may be useful in the clinic for preventing or treating any particular disease(s), in particular those diseases involving inflammation.
Harnett and Harnett in Biochemica et Biophysica Acta, 1539, (2001), 7–15 report investigations into the underlying mechanism of action of ES-62 and phosphorylcholine (PC). It is concluded that PC has various actions, including a number of immunomodulatory properties.
The prior art, at best, may only suggest that ES-62 has a role in the mediation of diseases involving an inflammatory response due to the effect of ES-62 on production of inflammatory cytokines. However, these investigations have been performed only in vitro, and no evidence is presented to show that ES-62 may be used to treat disorders associated with inflammation.
Evidence of such molecules having a clinical use has hitherto not been demonstrated, and thus an object of the present invention is to obviate and/or mitigate the current treatment inadequacies of diseases associated with inflammation.